ES2686704T3 - Pharmaceutical dosage forms - Google Patents

Abstract

A pharmaceutical dosage form for oral administration comprising (a) the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile as It is defined by formula (1) ** Formula ** or any pharmaceutically acceptable salt thereof, and (b) at least 30% by weight of microcrystalline cellulose based on the total weight of said pharmaceutical dosage form.

Description

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DESCRIPTION

Pharmaceutical dosage forms Field of the invention

The present invention relates to pharmaceutical dosage forms for oral administration comprising the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3- fluorobenzonitrile or any salt

pharmaceutically acceptable thereof. It also refers to processes for preparing said solid pharmaceutical dosage forms.

Background of the invention

Compound 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile and a method for its preparation was disclosed in WO2007 / 024945

Said compound is represented by the formula (1) and is referred to herein as a drug substance or compound of the formula (1).

image 1

(one)

The compound of the formula (1) has properties that modify the adrenal hormone and can be used to treat a disease or disorder characterized by the increase in stress hormone levels and / or decrease in androgen hormone levels in a subject, administering to the subject a therapeutically effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof.

In addition, the compound of the formula (1) can be used for the treatment of heart failure, cachexia, acute coronary syndrome, chronic stress syndrome, Cushing syndrome or metabolic syndrome, which comprises administering to the subject a therapeutically effective amount of a compound. represented by formula (I) or a pharmaceutically acceptable salt thereof.

Such medical uses of the compound of the formula (1) were described in WO2011 / 088188.

WO2013153129 discloses a combination of somatostatin analogs with the formula (1). This combination can be given for oral administration. Various crystalline and amorphous forms of the compound of the formula (1) and methods for preparing said forms are described in WO2013 / 109514. However, specific pharmaceutical compositions or pharmaceutical dosage forms for delivering the compound of the formula (1) to patients are not described in depth.

Summary of the Invention

Since each pharmaceutically active ingredient (API) has its own physical, chemical and pharmacological characteristics, a suitable pharmaceutical composition and dosage form has to be individually designed for each new pharmaceutically active ingredient.

The design of a pharmaceutical composition, a pharmaceutical dosage form, as well as a commercially viable pharmaceutical manufacturing process for the compound of the formula (1) is especially difficult due to (among other things) the following reasons:

Said compound, especially in its phosphate salt form, is very cohesive and is therefore affected by a strong tendency to aggregation. It was found that this aggregation was responsible for the poor and inhomogeneous distribution of the drug substance within the mixture with other ingredients.

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In addition, it was experienced that said drug substance was of poor pharmaceutical processability. For example, it was experienced that it was not sievable and had a poor flow (ffc 1.1).

Said compound, especially in its phosphate salt form, has a very low apparent density for the drug substance (0.1 to 0.3 g / ml) that is associated with problems of poor processability, for example, poor circulation, and the need for stages. special compaction in manufacturing with the aim of formulating said compound in an oral dosage form of reasonable size for the convenience of patients who have to swallow the resulting drug product.

Mainly due to its amine function, said compound is also affected by chemical instabilities, and incompatibilities with other ingredients.

Furthermore, said drug substance, especially in its phosphate salt form, is hygroscopic, which is again associated with stability problems.

Therefore, it is difficult to design a pharmaceutical composition for the compound of the formula (1) that is pharmaceutically processable and to design a pharmaceutical dosage form that is stable and of an acceptable size to be easily ingestible. In addition, it is difficult to design a manufacturing process that allows the compound of the formula (1) to be produced reliably on a commercially viable scale in pharmaceutical dosage forms that meet the high quality standards of human medicines at scale commercial.

One of the difficulties was to identify a suitable filler. There are basically three fillers that are predominantly used in the pharmaceutical field: lactose, mannitol and microcrystalline cellulose (MCC). However, it was found that the use of lactose as a filler causes chemical degradation products after compressing the compound of the formula (1) into tablets. The use of mannitol as an intragranular filling agent caused problems of adhesion and discoloration of the ribbon during the compaction stages. The use of MCC was considered as not suitable as a filler material for the compound of the formula (1) since it is known that MCC is associated with absorption effects of the drug substance due to its amorphous regions. Since MCC has a negatively charged surface, absorption effects are especially problematic for cationic drugs such as the compound of the formula (1). Also in this regard, the low apparent density (corresponding to a high surface area) of the cationic compound of the formula (1)) is problematic and makes the compound even more prone to absorption effects. Especially, at low dosing power such absorption effects can cause a significant loss of the availability of the drug substance. Consequently, all established fillers had to be ignored for the design of a pharmaceutical composition and pharmaceutical dosage form of the compound of the formula (1).

In view of the difficulties and considerations mentioned above, it was surprising that the present inventors found in counter-intuitive tests that the use of MCC as a filler material for the dosage forms of the compound of the formula (1) was possible. Surprisingly it was also found that the mixture of the compound of the formula (1) together with MCC returned to the drug, problematically very cohesive in a very pharmaceutically processable mixture.

Taking these surprising findings into account, the inventors herein provide the present invention in its following aspects.

In accordance with a first aspect of the invention, a pharmaceutical dosage form is provided for oral administration comprising

(a) the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile as defined by formula (1)

image2

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or any pharmaceutically acceptable salt thereof, and

(b) at least 30% by weight of microcrystalline cellulose based on the total weight of said pharmaceutical dosage form.

According to a second aspect of the invention, there is provided a process for the preparation of said pharmaceutical dosage form comprising the mixture of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1, 2- c] imidazol-5-yl] -3-fluorobenzonitrile with microcrystalline cellulose.

According to a third aspect of the invention, a pharmaceutical dosage form obtainable by said process is provided.

Detailed description of the invention

Hereinafter, the present invention is described in more detail and exemplified.

In aspects of the invention claimed the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile, also known herein as compound of the formula (1), is present as an enantiomer (R) of 4- [6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile. However, it can also be present as an enantiomer (S) of said compound, or as a mixture of said enantiomers. Preferably, said drug substance is present as (R) 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile enantiomer at least 50 %, more preferably at least 70%, even more preferably at least 90%, even more preferably at least 95%, even more preferably at least 98% based on the total amount to compound 4- [6,7-dihydro-5H -pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile in the pharmaceutical dosage form.

In aspects of the present invention, the drug substance is in its free form or in the form of any pharmaceutically acceptable salt, complex, co-crystal, hydrate or solvate thereof.

In one embodiment, the compound of the formula (1) is present in its free base form.

In another embodiment, the compound of the formula (1) is present as a phosphate salt; in yet another embodiment such as the mono-phosphate salt; In yet another embodiment such as the anhydrous mono-phosphate salt (1: 1 molar ratio of the compound of the formula (1) and phosphate. The mono-phosphate salt is also known as dihydrogen phosphate.

In one embodiment, the compound of the formula (1) is present as anhydrous mono phosphate salt in a polymorphic form characterized by an XRPD (X-ray powder diffraction) pattern comprising at least one or all of the following characteristic peaks (2-theta, angle of refraction, ± 0.2 °): 12.9 °, 16.3 °, 20.4 °. Said polymorphic form is described in WO2013 / 109514 A1 as "Form A". This last description provides the process for preparing this form and additional details on the characterization of this form (Example 1). In aspects of the present invention, the drug substance is present in the pharmaceutical dosage form, calculated based on its free base, from 0.5 to 20%, preferably from 0.5 to 10%, more preferably 1-8%, even more preferably 4 ± 1% by weight based on the total weight of said pharmaceutical dosage form. The pharmaceutical dosage form comprises microcrystalline cellulose, Ph.Eur., USP / NF, JP. In embodiments of the present invention, said MCC is present in at least 30%, 30 to 95%, 40 to 95%, 50 to 95%, 60 to 95%, 70 to 95%, 30 to 90%, 40 to 90%, 50 to 90%, 60 to 90%, 70 to 90%, 30 to 85%, 40 to 85%, 50 to 85%, 60 to 85%, or 70 to 85%. In a preferred embodiment the MCC is present from 30 to 95%, in a more preferred embodiment of 50 to 90%, in an even more preferred embodiment of 70 to 85%, in an even more preferred embodiment 77 ± 7% by weight with based on the total weight of said pharmaceutical dosage form.

The MCC can have an average particle size of 30 to 300 microns, 45 to 180 microns, 70 to 130 microns, or 100 ± 15 microns, measured by laser diffraction, said particle size is measured by laser light diffraction.

The MCC may have a weak apparent density of 0.2-0.5 g / mL 0.25-0.4 g / ml or 0.31 ± 0.03 g / mL.

In the exemplary embodiments, the MCC has an average particle size of 100 ± 15 microns and a weak apparent density of 0.31 ± 0.03 g / ml. Such MCC quality is commercially available as Avicel PH 102 from FMC BioPolymer (nominal particle size of 100 microns; humidity 3.0 to 5.0%; weak bulk density 0.28 to

0.33 g / cc) or Vivapur 102 from JRS Pharma (JRS = J. Rettenmaier &Sohne; average particle size by laser diffraction 100 microns; bulk density 0.28 to 0.33 g / cm3) and is also referred to herein as MK GR cellulose . This quality offers good tablet properties, for example, good tablet hardness.

The advantages of using MCC in the composition of a pharmaceutical dosage form comprising the drug substance of the formula (1) is that there are no chemical degradation reactions such as that observed for lactose, and there are no adhesion problems or problems of discoloration as observed for mannitol. Furthermore, the advantage of MCC is that it transforms the very cohesive drug substance, particularly the very cohesive phosphate salt of the compound of the formula (1) into a pharmaceutically well processable mixing material. For example, without MCC the drug substance cannot be screened, for example, through a sieve of 0.8 mm, despite its size

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The primary particle size (approximately 4 microns) is smaller than the sieve size. Due to the high tendency to add the drug substance it forms agglomerates of larger secondary particles (up to a size of 1 mm), which no longer pass the sieve. However, if, for example, the phosphate salt of the drug substance of the compound of the formula (1) is mixed with MCC in a proportion by weight (weight of compound of formula (1) as mono-phosphate salt: weight of MCC ) 1: 1 approximately, 1: 1.5 approximately, 1: 2 approximately, 1: 5 approximately, 1: 6 approximately, or with more MCC, a mixing material is obtained which can be easily screened through a sieve of 0.8 mm.

The pharmaceutical dosage forms according to the present invention may further comprise a slide, preferably comprises a slide, preferably said sliding agent is a silicon dioxide, more preferably said sliding agent is a colloidal silicon dioxide, Ph.Eur., USP / NF, JP.

The pharmaceutical dosage form according to the present invention is also provided wherein said sliding agent is present from 0.1 to 5%, preferably from 0.3 to 1.5%, more preferably from 0.6 ± 0.3% by weight based on the total weight of said form of pharmaceutical dosage

Preferably, said sliding agent is a colloidal silicon dioxide, also known as hydrophilic smoked silica, with a surface area per BET of 200 ± 25 m2 / g, for example as sold under the trade name Aerosil 200 Pharma by Evonik ( before Degussa; BET surface area of 200 ± 25 m2 / g; drying loss <2.5% by weight; pH 3.5 to 5.5).

The inventors of the present invention occasionally experienced clogging problems (at the end of the tablet, that is, the upper cap, is divided along the edge of the cap and the band of the tablet) and the low hardness values of the tablet with tablets of the phosphate salt of the drug substance of the formula (1) when the tablets are produced without a sliding agent or with only low levels of sliding agent (approximately 0.2% only). However, with approximately 0.5% by weight of colloidal silicon dioxide sliding agent based on the total final mixture ready for compression of the tablet, the clogging tendency was eliminated even at a high compression force and the hardness values of the tablet were They increased significantly. Therefore, the presence of a sliding agent in a pharmaceutical composition of the compound of the formula (1) has advantages, in particular when said sliding agent is present extragranularly.

In accordance with the present invention, the use of colloidal silica dioxide is provided to avoid problems of capping with tablets comprising the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c ] imidazol-5-yl] -3-fluorobenzonitrile.

In a preferred embodiment, the pharmaceutical dosage form according to the present invention comprises

(a) the drug substance 4 - [(5R) -6,7-dihydro-5 H -pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile or any pharmaceutically acceptable salt thereof, preferably said Drug substance is present as phosphate salt, more preferably as mono-phosphate salt,

(b) at least 30% by weight of microcrystalline cellulose based on the total weight of said pharmaceutical dosage form, and

(c) a sliding agent, preferably said sliding agent is colloidal silicon dioxide.

In a more preferred embodiment, the pharmaceutical dosage form according to the present invention comprises:

(a) 0.5 to 20%, calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2- c] imidazol-5-yl ] -3-fluorobenzonitrile present as monophosphate salt,

(b) 30-95% by weight of the microcrystalline cellulose,

(c) 0.1-5% by weight of colloidal silicon dioxide,

based on the total weight of said pharmaceutical dosage form.

In a more preferred embodiment, the pharmaceutical dosage form according to the present invention comprises:

(a) 0.5 to 20%, calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2- c] imidazol-5-yl ] -3-fluorobenzonitrile present as monophosphate salt,

(b) 30-95%, 50-95%, 70-90%, or 80 ± 5% by weight of microcrystalline cellulose,

(c) 0.1-5% by weight of colloidal silicon dioxide,

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based on the total weight of said pharmaceutical dosage form.

More specifically, in preferred embodiments of the present invention, the pharmaceutical dosage comprises an internal phase (also called intragranular phase) and an external phase (also called extragranular phase),

where the internal phase comprises:

(a) 0.5-20%, preferably 5-15%, more preferably 10 ± 2%, calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7-dihydro-5H- pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile present as a monophosphate salt, and

(b) 50-95%, preferably 70-90%, or more preferably 80 ± 5% by weight of microcrystalline cellulose, based on the total weight of the internal phase, and

and where the external phase comprises:

(c) 0.1-5%, preferably 0.2-1%, or more preferably 0.5 ± 5% by weight of colloidal silicon dioxide, based on the total weight of the final mixture.

In preferred embodiments of the present invention, the pharmaceutical dosage comprises an internal phase (also called intragranular phase) and an external phase (also called extragranular phase),

where the internal phase comprises:

(a) 5 to 15%, calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2- c] imidazol-5-yl ] -3-fluorobenzonitrile present as monophosphate salt, and

(b) 70-90% by weight of the microcrystalline cellulose, based on the total weight of the internal phase, and

and where the external phase comprises:

(c) 0.1-5% by weight of colloidal silicon dioxide, based on the total weight of the final mixture.

In more preferred embodiments of the present invention, the pharmaceutical dosage comprises an internal phase (also called intragranular phase) and an external phase (also called extragranular phase),

where the internal phase comprises:

(a) 5 to 15%, calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2- c] imidazol-5-yl ] -3-fluorobenzonitrile present as monophosphate salt, and

(b) 70-90% by weight of the microcrystalline cellulose, based on the total weight of the internal phase, and

and where the external phase comprises:

(c) 0.2-1% by weight of colloidal silicon dioxide, based on the total weight of the final mixture.

The terms internal phase or intragranular phase refer to the part of the composition that is granulated (for example, by wet granulation) or compacted (for example, roller compaction). The terms "external phase" or "extragranular phase" refer to the part of the composition that is added to the granulated or compacted internal phase to form together with said internal phase the final mixture.

The term "final blend" refers to the combined internal and external phase that is ready to be compressed into tablets or filled into capsules.

The pharmaceutical dosage form according to the present invention may further comprise mannitol, preferably further comprises mannitol, more preferably comprises mannitol in the external phase.

In preferred embodiments of the present invention, said mannitol is present in the pharmaceutical dosage form of 3 to 40%, preferably 5 to 40%, more preferably 5 to 15%, even more preferably 10 ± 2% by weight based on the total weight of said pharmaceutical dosage form.

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More specifically, in preferred embodiments of the present invention, said mannitol in said amounts is present in the external phase.

Preferably, said mannitol is in a quality suitable for direct compression (hereinafter also known as DC mannitol), for example Parteck M 200 by Merck.

In a particularly preferred embodiment of the present invention, the pharmaceutical dosage form comprises:

(a) 1 to 8%, preferably 4 ± 1% calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7- dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile present as monophosphate salt,

(b) 30-90%, preferably 77 ± 7% by weight of the microcrystalline cellulose,

(c) 0.1-5%, preferably 0.6 ± 0.3% by weight of colloidal silicon dioxide,

(d) 5-40%, preferably 10 ± 2% by weight of mannitol; optionally it also includes:

(e) 0.1 to 5%, preferably 2 ± 0.5% by weight of a disintegrant, preferably croscarmellose sodium (hereinafter also known as Na-CMC XL), for example Ac-Di-Sol from FMC Biopolymer), and

(f) 0.1-3%, preferably 1.5 ± 0.5% by weight of a lubricant, preferably magnesium stearate. based on the total weight of said pharmaceutical dosage form.

The pharmaceutical dosage form according to the present invention may be in the form of a powder, capsule or tablet, preferably it is in the form of a tablet.

In a preferred embodiment of the present invention, the pharmaceutical dosage form is in the form of a tablet and the tablet is coated with a film, that is, a film-coated tablet, preferably said film comprises polyvinyl alcohol and, optionally, a plasticizer and a pigment (for example, Opadry Premix by Colorcon).

In accordance with the second aspect of the present invention there is provided a process for the preparation of pharmaceutical dosage forms as described hereinbefore comprising the mixture of the drug substance 4 - [(5R) -6,7-dihydro -5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile with microcrystalline cellulose (MCC).

Preferably, said mixing of the drug substance with the MCC is carried out as a first stage of the process before any stage of screening, sieving, compaction, or compression.

Said mixing of the drug substance with MCC can be performed with MCC as the sole excipient or with MCC in combination with a sliding agent, preferably colloidal silicon dioxide, and optionally with a disintegrant.

Preferably, said method further comprises the use of a slip agent to prepare a mixture that is ready for tabletting.

In preferred embodiments of the present invention, said process is further characterized by the following process steps:

(1) mixing the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile together with microcrystalline cellulose, and optionally other ingredients such as colloidal silicon dioxide, a disintegrant, preferably croscarmellose, and a lubricant, preferably magnesium stearate (said ingredients constitute the internal phase), to obtain a compactable mixture by machine,

(2) compacting the compactable mixture by machine by dry granulation, preferably by roller compaction, to obtain a compacted material,

(3) mixing the compacted material with colloidal silicon dioxide, and optionally with other ingredients such as fillers, microcrystalline cellulose preferably, and / or mannitol more preferably microcrystalline cellulose and mannitol, a disintegrant, preferably croscarmellose sodium, and a lubricant , preferably magnesium stearate (said ingredients form the external phase), to obtain a machine compressible mixture (also known as the final mixture),

(4) compress the machine compressible mixture by using a tabletting machine to obtain the tablets.

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In a particularly preferred embodiment, the process is further characterized by the following process steps:

(1) mixing the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile together with microcrystalline cellulose, colloidal silicon dioxide, and a disintegrant, preferably croscarmellose, to obtain a mixture,

(2) sift the mixture from step (2), preferably through 0.5-2 mm, more preferably 0.6-1.0 mm, even more preferably 0.8 mm,

(3) mixing the screened mixture of step (3) with a lubricant, preferably magnesium stearate, to obtain a compactable mixture by machine,

(4) compacting the compactable mixture by machine of step (3) by dry granulation, preferably by roller compaction,

(5) sift the compacted mixture from step (4), preferably through 0.5-2 mm, more preferably 0.61.0 mm, even more preferably 0.8 mm,

(6) mixing the sieved compacted material from step (5) with microcrystalline cellulose, colloidal silicon dioxide, mannitol, and a disintegrant, preferably croscarmellose sodium, to obtain a mixture,

(7) mixing the mixture of step (6) with a lubricant, preferably magnesium stearate, to obtain a machine-compressible mixture,

(8) compress the machine compressible mixture from step (7) by using a tabletting machine to obtain nucleated tablets,

(9) coating the nucleated tablets of step (8) to obtain film-coated tablets.

In accordance with the third aspect of the present invention, pharmaceutical dosage forms are provided which can be obtained by any of the process embodiments as described hereinbefore.

In accordance with the fourth aspect of the invention, the use of microcrystalline cellulose to transform the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5il] - is provided 3-fluorobenzonitrile in a pharmaceutically processable material.

In accordance with a fifth aspect of the invention, the use of colloidal silicon dioxide is provided to prevent capping problems with tablets comprising the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1, 2- c] imidazol-5-yl] -3-fluorobenzonitrile.

In accordance with a sixth aspect of the invention, a pharmaceutical dosage form is provided for use in the treatment of Cusing disease or Cushing's syndrome.

According to a seventh aspect of the invention, a method of treating Cusing disease or Cushing's syndrome is provided, which comprises the step of administering a therapeutically effective amount of the pharmaceutical dosage form to a patient suffering from said disease.

Examples

Example 1: Tablet manufacturing

The manufacture of film-coated tablets of the drug substance of the formula (I) mono-phosphate salt is carried out according to the composition as shown in Table 1 below. The same composition is used for the manufacture of low potency tablets of doses of 5 mg, 10 mg, and 20 mg.

The manufacture of nucleated tablets consists of dry granulation, size selection, mixing and tablet formation steps:

1. Add approximately 50% of the internal phase microcrystalline cellulose (part 1) in an appropriate container and add the total amount of drug followed by the remaining 50% internal phase microcrystalline cellulose (part 2), Na-CMC-XL and Aerosil to obtain a drug sandwich between two layers of excipients; Mix the mixture in a diffusion mixer.

2. Sift the mixture from stage 1 through a sieve mill with oscillating bar (Frewitt MGW 520/6, sieve 0.8 mm, round wire, 57-104 rpm).

3. Screen magnesium stearate (hand sieve, mesh size 0.8 mm) and add it to the material of stage 2 and mix the combined materials in a diffusion mixer.

4. Compact the stage 3 mixture in a dry granulator, for example a roller compactor (Roller Bepex Hosokawa Pharmapaktor L-200 / 30P, compaction force of 18 kN, roller speed of 3-6 rpm (compaction roller of revolution), Speed of the revolution screw adapted to the compaction force).

5. Sift the compacted material from stage 4 through a sieve mill with oscillating bar (Frewitt mesh 5 MGW 520/6 0.8 mm, round wire, 57-104 rpm).

6. Sift the microcrystalline cellulose, mannitol, Na-CMC-XL and Aerosil (hand sieve, 0.8 mm mesh size) and add it to the material of step 5 and mix in a diffusion mixer.

7. Screen magnesium stearate (hand sieve, screen size 0.8 mm) and add it to the material of stage 6 and mix the combined materials in a diffusion mixer.

10 8. Compress the final mixture of step 7 using a rotary tablet forming machine (FETTE 1200i

TP09, 8 Euro B punches, compression force adjustment 1-40 kN to meet the white hardness of 80 N for 5 mg tablets, 100 N for 10 mg tablets, 160 N for 20 mg tablets).

9. Coat the stage 8 core tablet in a perforated tray coater (Glatt GC 750 or 1000).

A common final mixture for different dose concentrations can be manufactured by running a granulation and common mixture. The final mixture is divided according to the final batch size of tablets

nucleated by dose potency and compressed into a tablet press to produce the final nucleated tablet.

The resulting tablet cores are coated in a perforated coating tray with a ventilated side with a standard aqueous coating suspension.

20 Table 1: The formula for any dosing potency in the range of 5 to 20 mg, composition and batch quantity for

10 mg dosage potency tablets are given as representative examples, internal and external phase ingredients are listed separately

 Component

 Composition of the internal phase [%] Composition of the nucleated tablet [%] Composition of the film-coated tablet [%] Composition of 10 mg tablet [mg] Quantity per batch of 45.0 kg for 10 mg tablets [kg]

 Internal Phase

 Compound of formula (1) as mono-phosphate salt (corresponds to compound of formula (1) as free base)

 14.31a (10.00) 6.36a (4.44) 6.12a (4.27) 14,310a (10,000) 2,862a

 MK GR cellulose

 82.19 36.53 35.12 82.190 16.438

 200 PH spray

 0.50 0.22 0.21 0.500 0.100

 Na-CMC-XL

 2.00 0.89 0.85 2,000 0.100

 Magnesium stearate

 1.00 044 0.43 1,000 0.200

 Internal Phase Weight

 100.00 100,000

 External phase

 MK GR cellulose

   43.06 41.39 96.860 19.372

 Mannitol DC

   10.00 9.62 22,500 4,500

 200 PH spray

   0.50 0.48 1,120 0.224

 Na-CMC-XL

   1.00 0.97 2.260 0.452

 Magnesium stearate

   1.00 0.97 2.260 0.452

 Final Mix Weight. Core Tablet Weight

   100.00 225,000 45,000

 Pre-mix coating

     3.85 9,000 1,800

 Dyes

     3.85 9,000 1,800

 purified water

     - - 10.200b

 Weight of Film Coated Tablet

     100.00 234,000 46,800

 a The salt factor is 1,431. The amount of drug has to be adjusted if the content is <99.5%. The respective compensation is made by adjusting the content of Cellulose MK GR. b Water used during granulation is removed in the drying process.

Table 2: Formula for all dosing potencies in the range of 5 to 20 mg, composition and quantity per batch for 10 mg dosing tablets are given as representative examples, internal and external phase ingredients are listed as combined values

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 Component

 Composition of the nucleated tablet [%] Composition of the film-coated tablet [%] Composition of 10 mg tablet [mg] Quantity per batch of 45.0 kg for 10 mg tablets [kg]

 Compound of formula (1) as mono-phosphate salt (corresponds to compound of formula (1) as free base)

 6.36a (4.44) 6.12a (4.27) 14,310a (10,000) 2,862a

 MK GR cellulose

 79.59 76.51 179.050 35.810

 Mannitol DC

 10.00 9.62 22,500 4,500

 200 PH spray

 0.72 0.61 1.620 0.324

 Na-CMC-XL

 1.89 1.82 4.260 0.852

 Magnesium stearate

 1.44 1.40 3,260 0.652

 Nucleated Tablet Weight

 100.0% 225.00 45,000

 Pre-mix coating

   3.85 9,000 1,800

 Dyes

   3.85 9,000 1,800

 purified water

   - - 10.200b

 Weight of Film Coated Tablet

   100% 234,000 46,800

 a The salt factor is 1,431. The amount of drug has to be adjusted if the content is <99.5%. The respective compensation is made by adjusting the content of Cellulose MK GR. b Water used during granulation is removed in the drying process.

Table 3: Specifications and controls in process (IPC) for 5 mg, 10 mg and 20 mg nucleated tablets

 5 mg nucleated tablet [%] 10 mg nucleated tablet [%] 20 mg nucleated tablet [%]

 Weight (20 tablets)

 112.5 mg ± 15% 225.0 mg ± 15% 450 mg ± 10%

 Shape

 round round round

 Diameter

 7 mm 9 mm 11 mm

 Thickness (20 tablets)

 2.8 ± 0.3mm 3.4 ± 0.3mm 4.4 ± 0.3mm

 Hardness (20 tablets, white, average range)

 80 ± 20 N 100 ± 20 N 160 ± 30 N

 Friability (6.5 g tablets)

 No break No break No break

 <0.8% abrasion <0.8% abrasion <0.8% abrasion

 Disintegration time (6 units, without disc, water, 37 ° C)

 <15 min <15 min <15 min

Table 4: Specifications and controls in process (IPC) for 5 mg, 10 mg and 5 20 mg film-coated tablets

 5 mg film-coated tablet [%] 10 mg film-coated tablet [%] 20 mg film-coated tablet [%]

 Weight (20 tablets)

 118.00 mg ± 15% 234.00 ± 15% 446.00 mg ± 10%

 Shape

 round round round

 Diameter

 6.9 - 7.3 mm 8.9 - 9.3 mm 10.9 - 11.3 mm

 Thickness (20 tablets)

 2.9 ± 0.3 mm 3.5 ± 0.3 mm 4.5 ± 0.3 mm

 Friability (6.5 g tablets)

 No break No break No break

 Disintegration time (6 units, without disc, water, 37 ° C)

 <15 min <15 min <15 min

Claims (16)

5 10 fifteen twenty 25 30 1. A pharmaceutical dosage form for oral administration comprising (a) the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile as defined by formula (1) image 1 (one) or any pharmaceutically acceptable salt thereof, and (b) at least 30% by weight of microcrystalline cellulose based on the total weight of said pharmaceutical dosage form. 2. The pharmaceutical dosage form according to claim 1 wherein the microcrystalline cellulose is present from 30 to 95% by weight based on the total weight of said pharmaceutical dosage form. 3. The pharmaceutical dosage form according to any one of the preceding claims, wherein said drug substance is present as a phosphate salt, preferably as a mono-phosphate salt. 4. The pharmaceutical dosage form according to any one of the preceding claims, wherein said drug substance calculated based on its free base, is present from 0.5 to 20% by weight based on the total weight of said dosage form Pharmaceutical 5. The pharmaceutical dosage form according to any one of the preceding claims further comprising a sliding agent, preferably said sliding agent is a silicon dioxide, more preferably said sliding agent is a colloidal silicon dioxide. 6. The pharmaceutical dosage form according to claim 5 wherein said sliding agent is present from 0.1 to 5% by weight based on the total weight of said pharmaceutical dosage form. 7. The pharmaceutical dosage form according to any one of the preceding claims comprising (a) the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl] -3-fluorobenzonitrile present as phosphate salt, (b) at least 30% by weight of microcrystalline cellulose based on the total weight of said pharmaceutical dosage form, and (c) colloidal silicon dioxide. 8. The pharmaceutical dosage form according to claim 7 comprising: (a) 1 to 8%, calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2- c] imidazol-5-yl ] -3-fluorobenzonitrile present as monophosphate salt, (b) 30-95% by weight of the microcrystalline cellulose, (c) 0.3 - 1.5% by weight of colloidal silicon dioxide, based on the total weight of said pharmaceutical dosage form. 5 10 fifteen twenty 25 30 35 9. The pharmaceutical dosage form according to any one of the preceding claims further comprising mannitol. 10. The pharmaceutical dosage form according to claim 9 wherein said mannitol is present from 3 to 40% by weight, preferably 5 to 40% by weight based on the total weight of said pharmaceutical dosage form. 11. The pharmaceutical dosage form according to any one of the preceding claims comprising: (a) 4 ± 1%, calculated based on its free base, by weight of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1,2- c] imidazol-5-yl ] -3-fluorobenzonitrile present as monophosphate salt, (b) 77 ± 7% by weight of the microcrystalline cellulose, (c) 0.6 ± 0.2% by weight of colloidal silicon dioxide, (b) 10 ± 2% by weight of mannitol, and optionally also comprising: (e) 2 ± 0.5% by weight of a disintegrating agent, preferably croscarmellose sodium, and (f) 1.5 ± 0.5%, by weight of a lubricant, preferably magnesium stearate. based on the total weight of said pharmaceutical dosage form. 12. A process for the preparation of a pharmaceutical dosage form as defined by any one of the preceding claims comprising the mixture of the drug substance 4 - [(5R) -6,7-dihydro-5H-pyrrolo [1, 2- c] imidazol-5-yl] -3-fluorobenzonitrile with microcrystalline cellulose. 13. The process according to claim 12 wherein the mixing of the drug substance with microcrystalline cellulose is performed as a first stage of the process before any stage of screening, sieving, compaction, or compression. 14. The process according to claims 12 or 13 further comprising the use of a sliding agent to prepare a mixture that is ready for tabletting. 15. The process according to claims 12 to 14 further characterized by the following process steps: (1) mixing the drug substance together with the microcrystalline cellulose, and optionally additional ingredients such as a sliding agent, a disintegrating agent, and a lubricating agent, to obtain a compactable mixture by machine, (2) compacting the compactable mixture by machine by dry granulation, preferably by roller compaction, to obtain a compacted material, (3) mixing the compacted material with colloidal silicon dioxide, and optionally with additional ingredients such as microcrystalline cellulose, mannitol, a disintegrating agent, and a lubricant, to obtain a machine-understandable mixture, (4) compress the compressible mixture by machine by using a tabletting machine to obtain the tablets. 16. A pharmaceutical dosage form according to any one of claims 1-11 for use in the treatment of Cushing's disease or Cushing's syndrome.